Use of cannabinoids in the treatment of epilepsy

ABSTRACT

The present invention relates to the use of cannabidiol (CBD) in the treatment of Sturge Weber syndrome. CBD appears particularly effective in reducing all types of seizures and non-seizure symptoms in patients suffering with Sturge Weber syndrome. Preferably the CBD used is in the form of a highly purified extract of  cannabis  such that the CBD is present at greater than 98% of the total extract (w/w) and the other components of the extract are characterised. In particular the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w) and the propyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts of up to 1%. Alternatively, the CBD may be a synthetically produced CBD.

FIELD OF THE INVENTION

The present invention relates to the use of cannabidiol (CBD) in thetreatment of Sturge Weber syndrome. CBD appears particularly effectivein reducing all types of seizures and non-seizure symptoms in patientssuffering with Sturge Weber syndrome.

Preferably the CBD used is in the form of a highly purified extract ofcannabis such that the CBD is present at greater than 98% of the totalextract (w/w) and the other components of the extract are characterised.In particular the cannabinoid tetrahydrocannabinol (THC) has beensubstantially removed, to a level of not more than 0.15% (w/w) and thepropyl analogue of CBD, cannabidivarin, (CBDV) is present in amounts ofup to 1%. Alternatively, the CBD may be a synthetically produced CBD.

In use the CBD may be used concomitantly with one or more otheranti-epileptic drugs (AED). Alternatively the CBD may be formulated foradministration separately, sequentially or simultaneously with one ormore AED or the combination may be provided in a single dosage form.Where the CBD is formulated for administration separately, sequentiallyor simultaneously it may be provided as a kit or together withinstructions to administer the one or more components in the mannerindicated. It may also be used as the sole medication, i.e. as amonotherapy.

BACKGROUND TO THE INVENTION

Epilepsy occurs in approximately 1% of the population worldwide,(Thurman et al., 2011) of which 70% are able to adequately control theirsymptoms with the available existing anti-epileptic drugs (AED).However, 30% of this patient group, (Eadie et al., 2012), are unable toobtain seizure freedom using the AED that are available and as such aretermed as suffering from intractable or “treatment-resistant epilepsy”(TRE).

Intractable or treatment-resistant epilepsy was defined in 2009 by theInternational League Against Epilepsy (ILAE) as “failure of adequatetrials of two tolerated and appropriately chosen and used AED schedules(whether as monotherapies or in combination) to achieve sustainedseizure freedom” (Kwan et al., 2009).

Individuals who develop epilepsy during the first few years of life areoften difficult to treat and as such are often termedtreatment-resistant. Children who undergo frequent seizures in childhoodare often left with neurological damage which can cause cognitive,behavioral and motor delays.

Childhood epilepsy is a relatively common neurological disorder inchildren and young adults with a prevalence of approximately 700 per100,000. This is twice the number of epileptic adults per population.

When a child or young adult presents with a seizure, investigations arenormally undertaken in order to investigate the cause. Childhoodepilepsy can be caused by many different syndromes and genetic mutationsand as such diagnosis for these children may take some time.

The main symptom of epilepsy is repeated seizures. In order to determinethe type of epilepsy or the epileptic syndrome that a patient issuffering from, an investigation into the type of seizures that thepatient is experiencing is undertaken. Clinical observations andelectroencephalography (EEG) tests are conducted and the type(s) ofseizures are classified according to the ILAE classification describedbelow and in FIG. 1 .

The International classification of seizure types proposed by the ILAEwas adopted in 1981 and a revised proposal was published by the ILAE in2010 and has not yet superseded the 1981 classification. FIG. 1 isadapted from the 2010 proposal for revised terminology and includes theproposed changes to replace the terminology of partial with focal. Inaddition the term “simple partial seizure” has been replaced by the term“focal seizure where awareness/responsiveness is not impaired” and theterm “complex partial seizure” has been replaced by the term “focalseizure where awareness/consciousness is impaired”.

From FIG. 1 it can be seen that Generalised seizures, where the seizurearises within and rapidly engages bilaterally distributed networks, canbe split into six subtypes: Tonic-Clonic (grand mal) seizures; Absence(petit mal) Seizures; Clonic Seizures; Tonic Seizures; Atonic Seizuresand Myoclonic Seizures.

Focal (partial) seizures where the seizure originates within networkslimited to only one hemisphere, are also split into sub-categories. Herethe seizure is characterized according to one or more features of theseizure, including aura, motor, autonomic and awareness/responsiveness.Where a seizure begins as a localized seizure and rapidly evolves to bedistributed within bilateral networks this seizure is known as aBilateral convulsive seizure, which is the proposed terminology toreplace Secondary Generalized Seizures (generalized seizures that haveevolved from focal seizures and no longer remain localized).

Focal seizures where the subject's awareness/responsiveness is alteredare referred to as focal seizures with impairment and focal seizureswhere the awareness or responsiveness of the subject is not impaired arereferred to as focal seizures without impairment.

Epileptic syndromes often present with many different types of seizureand identifying the types of seizure that a patient is suffering from isimportant as many of the standard AED's are targeted to treat or areonly effective against a given seizure type/subtype.

One such childhood epilepsy is Sturge Weber syndrome (SWS). SWS is acongenital, non-familial disorder of unknown incidence. It is caused bya somatic genetic mutation in the gene GNAQ. It is characterized by acongenital facial birthmark and neurological abnormalities. Othersymptoms associated with SWS can include eye and internal organirregularities.

The clearest indication of SWS is a facial birthmark or “Port WineStain” which is present from birth. This typically involves at least oneupper eyelid and the forehead.

Neurological problems are caused by the development of excessive bloodvessel growth on the surface of the brain. These are located typicallyon the back region of the brain on the same side as the port winebirthmark. These growths create abnormal conditions for brain functionin the region.

Epilepsy is the most common early problem, (in around 80% of childrenwith SWS), often starting by one year of age. The convulsions usuallyappear on the opposite side of the body from the port wine stain andvary in severity. A weakening or loss of the use of one side of the bodymay develop opposite to the port wine stain. Developmental delay ofmotor and cognitive skills may also occur to varying degrees.

Other problems such as visual field defects, glaucoma and headachesoften occur in addition to neurological problems.

The anticonvulsant medications used to treat seizures in SWS includecarbamazepine; valproate; acetazolamide; diazepam; phenytoin; felbamate;tiagabine; levetiracetam; clonazepam; lamotrigine; primidone;gabapentin; phenobarbital; ethosuximide and zonisamide and topiramate.

Management of the non-seizure symptoms in SWS are also required.

Common AED defined by their mechanisms of action are described in thefollowing tables:

TABLE 1 Examples of narrow spectrum AED Narrow- spectrum AED MechanismIndication Phenytoin Sodium channel Complex partial Tonic-clonicPhenobarbital GABA/Calcium Partial seizures channel Tonic-clonicCarbamazepine Sodium channel Partial seizures Tonic-clonic Mixedseizures Oxcarbazepine Sodium channel Partial seizures Tonic-clonicMixed seizures Gabapentin Calcium channel Partial seizures Mixedseizures Pregabalin Calcium channel Adjunct therapy for partial seizureswith or without secondary generalisation Lacosamide Sodium channelAdjunct therapy for partial seizures Vigabatrin GABA Secondarilygeneralized tonic-clonic seizures Partial seizures Infantile spasms dueto West syndrome

TABLE 2 Examples of broad spectrum AED Broad- spectrum AED MechanismIndication Valproic acid GABA/Sodium First-line treatment for channeltonic-clonic seizures, absence seizures and myoclonic seizuresSecond-line treatment for partial seizures and infantile spasms.Intravenous use in status epilepticus Lamotrigine Sodium channel Partialseizures Tonic-clonic Seizures associated with Lennox-Gastaut syndromeEthosuximide Calcium channel Absence seizures Topiramate GABA/Sodiumchannel Seizures associated with Lennox-Gastaut syndrome ZonisamideGABA/Calcium/Sodium Adjunctive therapy in channel adults with partial-onset seizures Infantile spasm Mixed seizure Lennox-Gastaut syndromeMyoclonic Generalised tonic-clonic seizure Levetiracetam Calcium channelPartial seizures Adjunctive therapy for partial, myoclonic andtonic-clonic seizures Clonazepam GABA Typical and atypical absencesInfantile myoclonic Myoclonic seizures Akinetic seizures RufinamideSodium channel Adjunctive treatment of partial seizures associated withLennox- Gastaut syndrome

TABLE 3 Examples of AED used specifically in childhood epilepsy AEDMechanism Indication Clobazam GABA Adjunctive therapy in complex partialseizures Status epilepticus Myoclonic Myoclonic-absent Simple partialComplex partial Absence seizures Lennox-Gastaut syndrome StiripentolGABA Severe myoclonic epilepsy in infancy (Dravet syndrome)

Over the past forty years there have been a number of animal studies onthe use of the non-psychoactive cannabinoid cannabidiol (CBD) to treatseizures. For example, Consroe et al., (1982) determined that CBD wasable to prevent seizures in mice after administration of pro-convulsantdrugs or an electric current.

Studies in epileptic adults have also occurred in the past forty yearswith CBD. Cunha et al. reported that administration of CBD to eightadult patients with secondary generalized epilepsy resulted in a markedreduction of seizures in 4 of the patients (Cunha et al., 1980).

A study in 1978 provided 200 mg/day of pure CBD to four adult patients,two of the four patients became seizure free, whereas in the remainderseizure frequency was unchanged (Mechoulam and Carlini, 1978).

In contrast to the studies described above, an open label study reportedthat 200 mg/day of pure CBD was ineffective in controlling seizures intwelve institutionalized adult patients (Ames and Cridland, 1986).

Based on the fact that chronologically the last study to look at theeffectiveness of CBD in patients with epilepsy proved that CBD wasunable to control seizures, there would be no expectation that CBD mightbe useful as an anti-convulsant agent.

In the past forty years of research there have been over thirty drugsapproved for the treatment of epilepsy none of which are cannabinoids.Indeed, there appears to have been a prejudice against cannabinoids,possibly due to the scheduled nature of these compounds and/or the factthat THC, which is a known psychoactive, has been ascribed as apro-convulsant (Consroe et al., 1977).

The patent applications GB 2,487,712 describes the use of CBD withanti-epileptic drugs and WO 2015/193667 describes the use of CBD in thetreatment of treatment resistant epilepsy, in particular patients withFIRES are shown to benefit particularly from the treatment.

A paper published recently suggested that cannabidiol-enriched cannabismay be efficacious in the treatment of epilepsy. Porter and Jacobson(2013) report on a parent survey conducted via a Facebook group whichexplored the use of cannabis which was enriched with CBD in childrenwith treatment-resistant epilepsy. It was found that sixteen of the 19parents surveyed reported an improvement in their child's epilepsy. Thechildren surveyed for this paper were all taking cannabis that waspurported to contain CBD in a high concentration although the amount ofCBD present and the other constituents including THC were not known formany of the cases. Indeed, whilst CBD levels ranged from 0.5 to 28.6mg/kg/day (in those extracts tested), THC levels as high as 0.8mg/kg/day were reported.

A paper by Press et al. (2015) describes a review of 75 children andadolescents provided with oral cannabis extract. The responder rate forpatients with Lennox-Gastaut syndrome was very high at 88.9%, whereasthe rate for other childhood epilepsy syndromes such as Doose syndromeand Dravet syndrome were much lower or showed no improvement at all.

Providing children with TRE with a cannabis extract that comprises THC,which has been described as a pro-convulsant (Consroe et al., 1977), ata potentially psychoactive dose of 0.8 mg/kg/day, is a concern and assuch there is a need to determine whether CBD is in fact efficacious.

More recently in March 2016, GW Pharmaceuticals announced positiveresults in a Phase 3 study of CBD in the treatment of Dravet syndrome.

To date there have been no trials of CBD in children and young adultswith Sturge Weber syndrome.

BRIEF SUMMARY OF THE DISCLOSURE

In accordance with a first aspect of the present invention there isprovided Cannabidiol (CBD) for use in the treatment of Sturge Webersyndrome.

Preferably the CBD is used in the treatment of seizures, bothnon-convulsive and convulsive in Sturge Weber syndrome.

In a further embodiment the CBD is used in the treatment of non-seizuresymptoms in Sturge Weber syndrome.

Preferably the non-seizure symptoms are one or more of mood, behaviour,cognitive function and general quality of life.

In a further embodiment the CBD is for use in combination with one ormore concomitant anti-epileptic drugs (AED).

In a further embodiment the CBD is present as a highly purified extractof cannabis which comprises at least 98% (w/w) CBD. Preferably theextract comprises less than 0.15% THC. More preferably the extractfurther comprises up to 1% CBDV. More preferably still the extractfurther comprises between 0.1 and 1.0% CBDV.

In an alternative embodiment the CBD is present as a synthetic compound.

In a further embodiment of the invention the one or more AED is selectedfrom the group consisting of: carbamezapine, clobazam, clonazepam,clonidine, clorazepate, desmethylclobazam, diazepam, ethosuximide,felbamate, ketogenic diet, lacosamide, lamotrigine, levetiracetam,lorazepam, midazolam, N-desmethylclobazam, nordiazepam,oxycarbamezapine, perampanel, phenobarbital, phenytoin, pregabalin,rufinamide, stiripentol, topiramate, trazodone, vagus nerve stimulation,valproic acid, vigabatrin, and zonisamide.

Preferably the CBD is used in combination with at least two or more AEDand may be particularly beneficial when the patient is taking valproate.

Preferably the number of different anti-epileptic drugs that are used incombination with the CBD is reduced. Alternatively the dose ofanti-epileptic drugs that are used in combination with the CBD isreduced.

There are many side effects associated with the commonly used AED whichinclude dizziness, blurred vision, nausea, respiratory systemdepression, tiredness, headaches, and other motor side effects on thecentral nervous system. These side effects are particularly common ashigher doses or combinations of numerous AED are used. As such there isa need for an alternative medication that is able to reduce the numbersof seizures whilst at the same time exhibiting a safe side effectprofile.

Preferably the dose of CBD is greater than 5 mg/kg/day. Thus for a 15 kgpatient a dose of greater than 75 mg of CBD per day would be provided.Doses greater than 5 mg/kg/day such as greater than 10/mg/kg/day,greater than 15 mg/kg/day, greater than 20 mg/kg/day and greater than 25mg/kg/day are also envisaged to be effective.

Preferably the CBD is for use in the treatment of children and youngadults with Sturge Weber syndrome.

In accordance with a second aspect of the present invention there isprovided a method of treating Sturge Weber syndrome comprisingadministering cannabidiol (CBD) to a subject.

Preferably the subject is a human, more preferably a child or youngadult.

Preferably the CBD is used in the treatment of seizures, bothnon-convulsive and convulsive in Sturge Weber syndrome.

In a further embodiment the CBD is used in the treatment of non-seizuresymptoms in Sturge Weber syndrome.

Preferably the non-seizure symptoms are one or more of mood, behaviour,cognitive function and general quality of life.

Definitions

Definitions of some of the terms used to describe the invention aredetailed below:

The cannabinoids described in the present application are listed belowalong with their standard abbreviations.

TABLE 4 Cannabinoids and their abbreviations CBD Cannabidiol

CBDA Cannabidiolic acid

CBDV Cannabidivarin

CBDVA Cannabidivarinic acid

THC Tetrahydrocannabinol

The table above is not exhaustive and merely details the cannabinoidswhich are identified in the present application for reference. So farover 60 different cannabinoids have been identified and thesecannabinoids can be split into different groups as follows:Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (whichmay be novel cannabinoids or synthetically produced phytocannabinoids orendocannabinoids).

“Phytocannabinoids” are cannabinoids that originate from nature and canbe found in the cannabis plant. The phytocannabinoids can be isolatedfrom plants to produce a highly purified extract or can be reproducedsynthetically.

“Highly purified cannabinoid extracts” are defined as cannabinoids thathave been extracted from the cannabis plant and purified to the extentthat other cannabinoids and non-cannabinoid components that areco-extracted with the cannabinoids have been substantially removed, suchthat the highly purified cannabinoid is greater than or equal to 98%(w/w) pure.

“Synthetic cannabinoids” are compounds that have a cannabinoid orcannabinoid-like structure and are manufactured using chemical meansrather than by the plant.

Phytocannabinoids can be obtained as either the neutral (decarboxylatedform) or the carboxylic acid form depending on the method used toextract the cannabinoids. For example it is known that heating thecarboxylic acid form will cause most of the carboxylic acid form todecarboxylate into the neutral form.

“Treatment-resistant epilepsy” (TRE) or “intractable epilepsy” isdefined as per the ILAE guidance of 2009 as epilepsy that is notadequately controlled by trials of one or more AED.

“Childhood epilepsy” refers to the many different syndromes and geneticmutations that can occur to cause epilepsy in childhood. Examples ofsome of these are as follows: Dravet Syndrome; Myoclonic-AbsenceEpilepsy; Lennox-Gastaut syndrome; Generalized Epilepsy of unknownorigin; CDKL5 mutation; Aicardi syndrome; bilateral polymicrogyria;Dup15q; SNAP25; and febrile infection related epilepsy syndrome (FIRES);benign rolandic epilepsy; juvenile myoclonic epilepsy; Sturge WeberSyndrome (SWS); infantile spasm (West syndrome); and Landau-Kleffnersyndrome. The list above is non-exhaustive as many different childhoodepilepsies exist.

“Focal Seizures” are defined as seizures which originate within networkslimited to only one hemisphere. What happens during the seizure dependson where in the brain the seizure happens and what that part of thebrain normally does.

“Focal seizure where awareness/consciousness are impaired” has replacedthe term “complex partial seizure”. These seizures usually start in asmall area of the temporal lobe or frontal lobe of the brain and involveother areas of the brain within the same hemisphere that affectalertness and awareness. Most subjects experience automatisms during afocal seizure with impaired consciousness.

“Percentage decrease in seizure frequency” is defined as the number ofseizures at week 14 minus the number of seizures at baseline divided bythe number of seizures at baseline multiplied by 100. In patients whoare poor responders to existing AED any improvement in responseparticularly where the improvement is without side effects such as motorside effects on the central nervous system is highly desirable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the ILAE proposal for revised terminology for organizationof seizures and epilepsies.

DETAILED DESCRIPTION Preparation of Highly Purified CBD Extract

The following describes the production of the highly-purified (>98% w/w)cannabidiol extract which has a known and constant composition which wasused for the expanded access trials described in the Examples below.

In summary the drug substance used in the trials is a liquid carbondioxide extract of high-CBD containing chemotypes of Cannabis sativa L.which had been further purified by a solvent crystallization method toyield CBD. The crystallisation process specifically removes othercannabinoids and plant components to yield greater than 98% CBD.

The Cannabis sativa L. plants are grown, harvested, and processed toproduce a botanical extract (intermediate) and then purified bycrystallization to yield the CBD (drug substance).

Both the plant starting material is referred to as Botanical RawMaterial (BRM); the botanical extract is the intermediate; and theactive pharmaceutical ingredient (API) is CBD, the drug substance.

Both the botanical starting material and the botanical extract arecontrolled by specifications. The drug substance specification isdescribed in Table 5 below.

TABLE 5 CBD Specification Test Test Method Limits Appearance VisualOff-white/pale yellow crystals Identification A HPLC-UV Retention timeof major peak corresponds to certified CBD Reference StandardIdentification B GC-FID/MS Retention time and mass spectrum of majorpeak corresponds to certified CBD Reference Standard Identification CFT-IR Conforms to reference spectrum for certified CBD ReferenceStandard Identification D Melting Point 65-67° C. Identification ESpecific Conforms with certified CBD Optical Reference Standard; −110°Rotation to −140° (in 95% ethanol) Total Purity Calculation ≥98.0%Chromatographic HPLC-UV ≥98.0% Purity 1 Chromatographic GC-FID/MS ≥98.0%Purity 2 Other HPLC-UV Cannabinoids: CBDA NMT 0.15% w/w CBDV NMT 1.0%w/w Δ⁹ THC NMT 0.15% w/w CBD-C4 NMT 0.5% w/w Residual Solvents: GCAlkane NMT 0.5% w/w Ethanol NMT 0.5% w/w Residual Water Karl Fischer NMT1.0% w/w NMT—Not more than

The purity of the CBD drug substance achieved is greater than 98%. Theother cannabinoids which may occur in the extract are: CBDA, CBDV,CBD-C4 and THC.

The CBDV may be present in the drug substance at an amount of between0.1 and 1%.

Distinct chemotypes of Cannabis sativa L. plant have been produced tomaximize the output of the specific chemical constituents, thecannabinoids. One type of plant produces predominantly CBD. Only the(−)-trans isomer occurs naturally. Furthermore during purification thestereochemistry of CBD is not affected.

Production of the Intermediate

An overview of the steps to produce a botanical extract, theintermediate, are as follows:

-   -   1. Growing    -   2. Decarboxylation    -   3. Extraction No. 1—using liquid CO2    -   4. Extraction No. 2—‘winterization’ using ethanol    -   5. Filtration    -   6. Evaporation

High CBD chemovars were grown, harvested and dried and stored in a dryroom until required. The botanical raw material (BRM) was finely choppedusing an Apex mill fitted with a 1 mm screen. The milled BRM was storedin a freezer for up to 3 months prior to extraction.

Decarboxylation of CBDA to CBD was carried out using a large Heraeustray oven. The decarboxylation batch size in the Heraeus isapproximately 15 Kg. Trays were placed in the oven and heated to 105°C.; the BRM took 96.25 minutes to reach 105° C. Held at 105° C. for 15Minutes. Oven then set to 150° C.; the BRM took 75.7 minutes to reach150° C.; BRM held at 150° C. for 130 Minutes. Total time in the oven was380 Minutes, including 45 minutes cooling and 15 Minutes venting.

Extraction No 1 was performed using liquid CO2 at 60 bar/10° C. toproduce botanical drug substance (BDS).

The crude CBD BDS was winterised in Extraction No 2 under standardconditions (2 volumes of ethanol at minus 20° C. for around 50 hours).The precipitated waxes were removed by filtration and the solventevaporated using the rotary evaporator (water bath up to 60° C.) toyield the BDS, which was then used for crystallisation to produce thetest material.

Production of the Drug Substance

The manufacturing steps to produce the drug substance from theintermediate

-   -   botanical extract are as follows:    -   1. Crystallization using C5-C12 straight chain or branched        alkane    -   2. Filtration    -   3. Optional recrystallization from C5-C12 straight chain or        branched alkane    -   4. Vacuum drying

Intermediate botanical extract (12 kg) produced using the methodologyabove was dispersed in C5-C12 straight chain or branched alkane (9000ml, 0.75 vols) in a 30 litre stainless steel vessel.

The mixture was manually agitated to break up any lumps and the sealedcontainer then placed in a freezer for approximately 48 hours.

The crystals were isolated by vacuum filtration, washed with aliquots ofcold C5-C12 straight chain or branched alkane (total 12000 ml), anddried under a vacuum of <10 mb at a temperature of 60° C. until drybefore submitting the drug substance for analysis.

The dried product was stored in a freezer at minus 20° C. in apharmaceutical grade stainless steel container, with FDA food gradeapproved silicone seal and clamps.

Production of the Drug Product

The drug product is presented as an oral solution. The oral solutionpresentation contains 25 mg/ml or 100 mg/ml CBD, with the excipientssesame oil, ethanol, sucralose and flavouring. Two product strengths areavailable to allow dose titration across a wide dose range.

The 25 mg/ml solution is appropriate at lower doses and the 100 mg/mlsolution at higher doses.

The drug product formulation is as described in Table 6 below:

TABLE 6 Drug Product specification Reference Qualitative to QualityComponent Composition Function Standard Cannabidiol (CBD) 25 mg/ml orActive In-house 100 mg/ml Anhydrous ethanol 79.0 mg/ml* Excipient Ph.Eur. Sucralose 0.5 mg/ml Sweetener In-house Strawberry flavouring 0.2mg/ml Flavouring In-house Sesame oil q.s to 1.0 ml Excipient Ph. Eur.

The drug substance, CBD is insoluble in water. Sesame oil was selectedas an excipient to solubilize the drug substance.

A sweetener and fruit flavouring are required to improve palatability ofthe sesame oil solution.

Ethanol was required to solubilize the sweetener and the flavouring.

The composition can be substantially equivalent, by which is meant thefunctional ingredients can vary from the qualitative compositionspecified in Table 6 by an amount of up to 10%.

Example 1 below describes the use of a highly purified cannabis extractcomprising cannabidiol (CBD). Cannabidiol is the most abundantnon-psychoactive cannabinoid in the selected chemovar. Previous studiesin animals have demonstrated that CBD has anticonvulsant efficacy inmultiple species and models.

Example 1 describes data produced in an expanded access treatmentprogram in children with SWS.

Example 1: Efficacy of Cannabidiol in Reducing Seizures and OtherSymptoms in Children and Young Adults with Sturge Weber SyndromeMaterials and Methods

Four subjects with SWS brain involvement and refractory epilepsy wereenrolled in an expanded access compassionate use program for CBD. Thesesubjects were treated with a highly purified extract of cannabidiol(CBD) obtained from a cannabis plant. Frequency of seizures was recordedat each visit, as were reported quality of life changes, including mood,behaviour, and cognitive function.

Data were compared in the 56-day pre-treatment period, the 56-day periodafter starting maintenance dose (Week 14), and at most recent visit.

The participants in the study were taking at the time of entry into thestudy between one and four concomitant AEDs.

Patient 1 was taking leviteracetam alone. Patient 2 was takingleviteracetam, valproate, felbamate and clobazam. Patient 3 was takingvalproate and topiramate. Patient 4 was taking oxycarbamazepine andlacosamide.

CBD was administered at a target dose of 15-25 mg/kg/day.

All patients entered a baseline period of 14 weeks whenparents/caregivers kept prospective seizure diaries, noting allcountable seizure types.

The patients then received a highly purified CBD extract (greater than98% CBD w/w) in sesame oil, of known and constant composition, at a doseof 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED)regimen.

The daily dose was gradually increased by 2 to 5 mg/kg increments up toa maximum dose of 25 mg/kg/day.

Patients were seen at regular intervals of 2-4 weeks. Laboratory testingfor hematologic, liver, kidney function and concomitant AED levels wasperformed at baseline, and after every 4 weeks of CBD therapy.

Results

At Week 14, all 4 patients had a reduction in the number of seizures ofbetween 10 and 90%.

A summary of the improvement in total seizure frequency, based on 14weeks of treatment are summarized in Table 7 below.

TABLE 7 Summary of total seizure frequency after 14 weeks of treatmentBaseline Week 14 Decrease in Patient (number of (number of seizurenumber seizures) seizures) frequency (%) 1 67 60 10 2 6 1 83 3 10 1 90 46 4 33

Table 7 shows that after 14 weeks of therapy, two patients experienced adramatic reduction in seizure frequency at 83 and 90% reduction. Both ofthe other patients with SWS experienced a decrease in seizures albeit toa lesser extent. These data infer that the CBD is very effective atreducing seizure in this type of epilepsy syndrome.

In addition three of the four patients (patients 2, 3 and 4) reportedimproved quality of life, whereas one (patient 1) remained unchanged.These included improvements in mood and behaviour in two subjects(patient 2 and 3) and improvements in cognitive function in threesubjects (patients 2, 3 and 4).

CONCLUSIONS

These data indicate that CBD is effective in the treatment of SWS.

Particular benefits include reducing in seizure frequency in a highproportion of patients with SWS that do not respond well to existingAED.

Indeed it is interesting to note that the two patients receivingvalproate (patient numbers 2 and 3) obtained the greatest benefit andthe patient with the least benefit was only taking one AED whilst theremainder of the patients were taking at least two concomitant AED.

It was surprising that in this group of patients which aretreatment-resistant such a high number were able to gain an effect. Thefact that three quarters of the patients benefitted from a reduction inthe number of seizures that they suffered from was remarkable. Thismight be a consequence of a synergy with valproate or another AED or thefact that more than one AED was used concomitantly with the CBD.

It is also surprising that the patients a high proportion of thepatients additionally experienced improvements in other areas of theirdisease such as improvements in mood, behaviour, cognitive function andgeneral quality of life.

REFERENCES

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1. A method of treating Sturge Weber syndrome in a subject, comprising administering to the subject a therapeutically effective amount of cannabidiol (CBD) drug substance, wherein the CBD drug substance comprises at least 98% (w/w) CBD.
 2. The method of claim 1, wherein the treating comprises treating seizures in a subject having Sturge Weber syndrome.
 3. The method of claim 1, wherein the treating comprises treating non-seizure symptoms in a subject having Sturge Weber syndrome.
 4. The method of claim 3, wherein the non-seizure symptoms are one or more of mood, behavior, cognitive function and general quality of life.
 5. The method of claim 1, wherein the drug substance comprises less than 0.15% tetrahydrocannabinol (THC).
 6. The method of claim 1, wherein the drug substance further comprises up to 1% cannabidivarin (CBDV).
 7. The method of claim 1, wherein the drug substance further comprises between 0.1 and 1.0% CBDV.
 8. The method of claim 1, wherein the CBD is present as a synthetic compound.
 9. The method of claim 1, wherein the dose of CBD is about 10 mg/kg/day.
 10. The method of claim 1, wherein the subject is a child or young adult.
 11. The method of claim 1, wherein the dose of CBD ranges from about 5 mg/kg/day to about 25 mg/kg/day.
 12. The method of claim 1, wherein the dose of CBD is about 20 mg/kg/day.
 13. The method of claim 1, wherein the dose of CBD is about 25 mg/kg/day.
 14. The method of claim 1, wherein the CBD drug substance is a highly purified extract of cannabis.
 15. The method of claim 2, wherein the dose of CBD ranges from about 5 mg/kg/day to about 25 mg/kg/day.
 16. The method of claim 2, wherein the dose of CBD is about 10 mg/kg/day.
 17. The method of claim 2, wherein the dose of CBD is about 20 mg/kg/day.
 18. The method of claim 2, wherein the dose of CBD is about 25 mg/kg/day.
 19. The method of claim 3, wherein the dose of CBD ranges from about 5 mg/kg/day to about 25 mg/kg/day.
 20. The method of claim 3, wherein the dose of CBD is about 10 mg/kg/day.
 21. (canceled)
 22. (canceled) 